JPH11222432A - Preparation for external use containing amide derivative inducing interferon - Google Patents

Preparation for external use containing amide derivative inducing interferon

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Publication number
JPH11222432A
JPH11222432A JP2165298A JP2165298A JPH11222432A JP H11222432 A JPH11222432 A JP H11222432A JP 2165298 A JP2165298 A JP 2165298A JP 2165298 A JP2165298 A JP 2165298A JP H11222432 A JPH11222432 A JP H11222432A
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group
represents
external preparation
solution
dissolution
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Inventor
Takao Iizuka
Ryoichi Nanba
Mieko Ueda
Eiji Watanabe
美江子 上田
英二 渡辺
亮一 難波
貴夫 飯塚
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Terumo Corp
テルモ株式会社
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Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for external use having both suppressing actions on eosinophil infiltration due to the strong interferon induction activity and excellent percutaneous absorptivity by including a specific amide derivative (an acid addition salt), a dissolution and absorption promoter and a base therein. SOLUTION: This preparation for external use is obtained by including (A) 0.001-10% of an amide derivative (an acid addition salt) represented by the formula R1 and R2 are each a 1-6C (branched)alkyl or the like; X and Y are each O, S(O)p [(p) is 0-2] or the like; Z is an aromatic ring, a heterocyclic ring or the like; R3 is H, a (substituted)phenyl or the like; (g), (i) and (k) are each 0-6; (h), (j) and (l) are each 0 or 1; (m) is 0-5; (n) is 2-12}, (B) a dissolution and absorption promoter and (C) a base. Alcohols (ethanol, 1,3-butanol, glycerol, etc.), higher fatty acids (isostearic acid, oleic acid, etc.), etc. are cited as the ingredient B. An ointment, a cream, a lotion, a gel, a plaster, a spray etc. are cited as the dosage form of the preparation for external use.

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【発明の属する技術分野】本発明は、強力にインターフェロンを誘起し、皮膚好酸球浸潤反応を抑制するアトピー性皮膚炎などの治療剤として有用な新規なアミド誘導体を含有する外用剤である。 The present invention relates are strongly induce interferon, external preparation containing useful novel amide derivatives skin eosinophilic infiltration reaction as a therapeutic agent such as suppressing atopic dermatitis.

【0002】 [0002]

【従来の技術】アトピー性皮膚炎の治療には、従来より基本的にステロイド剤の外用と抗ヒスタミン剤あるいは抗アレルギー剤の内服が行われており、その他、減感作療法、アレルゲン(ダニ・食物)除去療法、PUVA Treatment of the Related Art atopic dermatitis, conventionally have been basically conducted oral topical and antihistamines or antiallergic agents steroids, other, desensitization therapy, allergens (Dani food) removal therapy, PUVA
(ソラレン−長波長紫外線照射)療法、細菌ワクチン療法などが試みられている。 (Psoralen - UVA radiation) therapy, such as bacterial vaccine therapy has been attempted. しかし、いずれも決め手となるものではなく、特にステロイド外用剤は、切れ味は良いが長期連投による皮膚の萎縮・毛細血管拡張・潮紅・ However, none of them is decisive, especially topical steroids, the sharpness is good, but flushing atrophy, telangiectasia, of the skin due to long-term Rento -
紫斑・易感染性などの副作用が問題となっている。 Side effects such as bruising, susceptibility to infection has become a problem.

【0003】最近、アトピー性皮膚炎治療の方向はステロイドから作用メカニズムが新規なサイトカイン療法に向かいつつある(中川秀巳,臨床免疫,27[supple 16] 59 Recently, the mechanism of action from atopic dermatitis direction steroids are being directed to a novel cytokine therapy (Nakagawa Shigerumi, Clinical Immunology, 27 [supple 16] 59
7-602,1995, 小林祥子ら,臨床免疫,27,[supple 16] 603 7-602,1995, Sachiko, et al. Kobayashi, Clinical Immunology, 27, [supple 16] 603
-609,1995)。 -609,1995). アトピー性皮膚炎患者においては、Th1 In patients with atopic dermatitis, Th1
ヘルパー細胞とTh2ヘルパー細胞のバランスの不均衡すなわちTh2細胞優位の状態にあり、Th2細胞からのインターロイキン−4やインターロイキン−5などのサイトカインの産生増大の結果、IgE産生や好酸球等の炎症細胞の分化・増殖・浸潤を増強し炎症が惹起されるという説が有力となっている。 Located unbalanced i.e. Th2 cells dominant state of balance of helper cells and Th2 helper cells, the interleukin-4 and interleukin-5 cytokines such as increased production from Th2 cells results, IgE production and the like eosinophils the theory that inflammation enhances the differentiation and proliferation and infiltration of inflammatory cells is induced has become a leading. 一般に、感作されたヒトの皮膚に抗原を投与すると投与直後と4〜8時間後に最大となり24〜48時間持続する皮膚反応が生じる。 In general, the skin reaction that persists immediately after administration and administering the antigen to human skin sensitized and becomes maximum 24-48 hours after 4-8 hours occurs. 前者を即時型反応(IgE-肥満細胞が関与)、後者を遅発型アレルギー反応と呼ぶ。 The former immediate reaction (IgE-mast cell involvement), referred to as late allergic reactions of the latter. 特に遅発型反応は喘息を含むアレルギー疾患の病態と密接な関係があると指摘されている。 Especially late reaction is pointed out that closely related to pathogenesis of allergic diseases including asthma. 遅発型反応のメカニズムは永らく不明であったが、今日では Mechanism of delayed-type reaction was Nagaraku unknown, Today
IgE-肥満細胞が関与するI型アレルギー反応における時間的に遅れた相、すなわちlate phase reactionof the Phase temporally delay in the type I allergic reaction IgE- mast cells are involved, namely late phase reactionof the
typeI allergy であり、Th2ヘルパー細胞優位による好酸球浸潤が深く関わっていると考えられるようになった(黒沢元博,臨床免疫,27(5),564-574,1995)。 typeI an allergy, Th2 helper cells advantage by eosinophil infiltration now considered to be deeply involved (Motohiro Kurosawa, Clinical Immunology, 27 (5), 564-574,1995). Th Th
1ヘルパー細胞とTh2ヘルパー細胞のバランスはインターフェロンによって調節されており、インターフェロン(α、γ)はTh0細胞のTh1細胞への分化を促進する。 1 Balance helper cells and Th2 helper cells is regulated by interferon, interferon (alpha, gamma) promotes differentiation into Th1 cells Th0 cells. 従って、Th2細胞優位を是正するインターフェロン(α、γ)がアトピー性皮膚炎の治療に試みられるようになってきた。 Therefore, interferons to correct the Th2 cells dominant (alpha, gamma) has come to be tried in the treatment of atopic dermatitis.

【0004】インターフェロン療法の主流はリコンビナントなインターフェロンα( Paukkonen K.et.al.:Act [0004] The mainstream of interferon therapy recombinant interferon-α (Paukkonen K.et.al.:Act
a. Derm. Venereol.73,141-142,1993)やインターフェロンγ( Hanifin JM:J.Am.Dermatol.28,189-197,199 .. A Derm Venereol.73,141-142,1993) and interferon-γ (Hanifin JM: J.Am.Dermatol.28,189-197,199
3, Nishioka K.et.al.:J.Dermatol. 22(3),181-185,199 3, Nishioka K.et.al.:J.Dermatol. 22 (3), 181-185,199
5)の皮下注射であり、皮膚症状の改善と血中好酸球数の減少が報告されている。 5) a subcutaneous injection, improvement and reduction in blood eosinophil counts skin conditions have been reported. インターフェロンは免疫強化作用を有するのでステロイドでよく認められる易感染性等の副作用は認められない。 Interferon is not observed side effects of compromised or the like that is well recognized in the steroid because it has an immune strengthening action. しかし、高コストであることと別の副作用(発熱、感冒様症状、頭痛)が発現するという点でまだ満足できる薬物とは言えない。 However, it and the other side effects which is a high cost (fever, cold-like symptoms, headache) can not be said to still satisfactory drug in terms of expression.

【0005】インターフェロンそれ自身はまだ幾つかの問題を残しているが、低分子化合物のインターフェロン誘起剤が開発されればその局所適用(外用)によってステロイド外用剤及びインターフェロン注射剤の抱えている問題(コストと副作用)を解決できる可能性は高い。 [0005] Interferon is itself still remains a number of problems, suffer of topical corticosteroids and interferon injections by if interferon inducer of the low molecular compound is developed its topical application (topical) issues ( possibility to solve the cost and side effects) is high.
これまでインターフェロンを誘起する化合物が幾つか公知となっている。 Compounds which induce interferon is made with several well-known up to now. 例えば、1−置換−1H−イミダゾ[4,5−c]キノリン−4−アミン類としては、抗ウイルス剤である1−イソブチル−1H−イミダゾ[4, For example, the 1-substituted -1H- imidazo [4,5-c] quinolin-4-amine, is an antiviral agent 1-isobutyl--1H- imidazo [4,
5−c]キノリン−4−アミン(イミキモド)を始めとして幾つか知られている(欧州特許第145340号、 5-c] known some including the quinolin-4-amine (imiquimod) (European Patent No. 145340,
米国特許第4689338号、米国特許第469834 US Patent No. 4689338, US Pat. No. 469,834
8号、米国特許第4929624号、欧州特許第385 No. 8, US Pat. No. 4,929,624, European Patent No. 385
630号、米国特許第5346905号等)。 630, U.S. Pat. No. 5,346,905, etc.).

【0006】それらのヒトでのインターフェロン誘起活性は低く、また好酸球浸潤抑制作用も記載されていない。 [0006] Interferon-induced activity in those humans is low, also not described infiltration inhibitory action eosinophils. したがって、高いインターフェロン誘起活性を持つ化合物を含有し、皮膚局所において好酸球の浸潤を抑制する外用製剤が望まれる。 Accordingly, it contains a compound having a high interferon-induced activity, suppressing external preparations infiltration of eosinophils is desired in the skin topically.

【0007】 [0007]

【発明が解決しようとする課題】従って本発明は、強力なインターフェロン誘起活性による好酸球浸潤抑制作用と優れた経皮吸収性を有し、従ってアトピー性皮膚炎などに有効な新規な化合物を含有する外用剤を提供することにある。 [SUMMARY OF THE INVENTION Accordingly the present invention provides a strong eosinophil infiltration suppressing action of interferon-induced activity and has excellent percutaneous absorbability, thus effective novel compounds such as atopic dermatitis to provide an external preparation containing.

【0008】 [0008]

【課題を解決するための手段】上記の課題を解決する本発明は以下の通りである。 To solve the above problems SUMMARY OF THE INVENTION The present invention is as follows.

【0009】本発明の外用剤に含まれる化合物は下記式Iで示されるアミド誘導体及びその医薬的に許容しうる酸付加塩であり、これらを少なくとも効果を発揮するために十分な量の溶解・吸収促進剤を含有する外用剤を提供する。 [0009] compound contained in the external preparation of the present invention is an amide derivative and the pharmaceutically acceptable acid addition salt represented by the following formula I, dissolved in an amount sufficient to exert the least effect these - to provide an external preparation containing an absorption enhancer.

【0010】 [0010]

【化2】 ## STR2 ##

【0011】(式I中、R 1およびR 2は炭素数1から6 [0011] (wherein I, R 1 and R 2 are from 1 to 6 carbon atoms
の分岐していてもよいアルキル基を表し、またR 1とR 2 It represents the optionally branched alkyl group, and R 1 and R 2
は一つになって環を形成していてもよい。 May form a ring becomes one. またR 1またはR 2のどちらかが、X、Yあるいはメチレン鎖中の任意の原子と一つになって環を形成していてもよい。 Also either R 1 or R 2, X, may become one and any atom in Y, or a methylene chain to form a ring.

【0012】XおよびYは独立して、酸素原子、S(О) [0012] X and Y are independently an oxygen atom, S (o)
p(pは0から2の整数を表す。)、NR 4 、CR 5 =C p (p is an integer of 0 to 2.), NR 4, CR 5 = C
6 、CR 78あるいは置換されていてもよいフェニレン基を表す。 Represents a R 6, CR 7 R 8 or optionally substituted phenylene group. ここで、R 4 、R 5 、R 6 、R 7およびR 8は独立して、水素原子、低級アルキル基、水酸基、低級アルコキシ基、アミノ基、モノあるいはジ低級アルキル置換アミノ基、カルボキシル基、低級アルコキシカルボニル基、置換されていてもよい芳香環基、あるいは置換されていてもよい複素環基を表す。 Wherein, R 4, R 5, R 6, R 7 and R 8 are independently hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, mono- or di-lower alkyl-substituted amino group, a carboxyl group, lower alkoxycarbonyl group, a optionally substituted aromatic ring group or an optionally substituted heterocyclic group.

【0013】Zは芳香環または複素環を表し、低級アルキル基、水酸基、低級アルコキシ基あるいはハロゲンのような置換基を有していてもよい。 [0013] Z represents an aromatic ring or a heterocyclic ring, lower alkyl group, a hydroxyl group, which may have a substituent such as a lower alkoxy group or a halogen.

【0014】R 3は水素原子、置換されていてもよいフェニル基、低級アルキル基(フェニル基、フェノキシ基、ベンジルオキシ基、低級アルコキシ基、アミノ基、 [0014] R 3 is a hydrogen atom, an optionally substituted phenyl group, a lower alkyl group (a phenyl group, a phenoxy group, a benzyloxy group, a lower alkoxy group, an amino group,
モノあるいはジ低級アルキル置換アミノ基、カルボキシル基、あるいは低級アルコキシカルボニル基で置換されていてもよい。 Mono- or di-lower alkyl-substituted amino group, it may be substituted with a carboxyl group or a lower alkoxycarbonyl group. )を表す。 ) Represents the.

【0015】g、iおよびkは独立して0から6の整数を表し、h、jおよびlは独立して0または1を表し、 [0015] g, i and k represents an integer of from 0 independently 6, h, j and l independently represents 0 or 1,
mは0から5の整数を、nは2から12の整数を表す。 m represents an integer of 0 to 5, n represents an integer of from 2 to 12. ) 式Iで示されるアミド誘導体に医薬的に許容しうる酸付加塩としては、塩酸、臭化水素酸、硫酸、硝酸、リン酸、酢酸、乳酸、マレイン酸、フマル酸、クエン酸、リンゴ酸、酒石酸、シュウ酸、メタンスルホン酸、p−トルエンスルホン酸などの塩が挙げられ、常法により調製される。 ) Formula Pharmaceutically acceptable acid addition salts to an amide derivative represented by I, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, lactic, maleic, fumaric acid, citric acid, malic acid , tartaric acid, oxalic acid, methanesulfonic acid, and the like salts p- toluenesulfonic acid, is prepared by a conventional method.

【0016】式Iで示されるアミド誘導体の多くは、分子内に不斉炭素を有しラセミ混合物であるが、必要に応じて光学分割、不斉合成などの方法によって各光学活性体を単離し、利用することが可能である。 [0016] Many of the amide derivatives of Formula I, is a racemic mixture have an asymmetric carbon in the molecule, apart optical optionally divided, by a method such as asymmetric synthesis of each optically active form single , it is possible to use.

【0017】 [0017]

【発明の実施の形態】本発明の式Iで示されるアミド誘導体及びその医薬的に許容される酸付加塩(以下、酸付加塩と略す)は、アトピー性皮膚炎治療剤として投与することができる。 Amide derivatives of formula I of the embodiment of the present invention and their pharmaceutically acceptable acid addition salt thereof (hereinafter, referred to as acid addition salts) may be administered as atopic dermatitis therapeutic agent it can.

【0018】外用剤の剤形は、軟膏、クリーム、ローション、ゲル剤、貼付剤、スプレーなどが挙げられる。 [0018] The dosage form of the external preparations, ointments, creams, lotions, gels, patches, such as spray and the like. いずれの剤形においても、調製の際に適当な医薬・製剤的に許容しうる添加物を用いることができる。 In any dosage form, it may be used a suitable pharmaceutical, pharmaceutically additives acceptable in the preparation. 添加物としては、賦形剤、結合剤、滑沢剤、崩壊剤、希釈剤、風味剤、着色剤、溶解剤、懸濁剤、乳化剤、保存剤、緩衝剤、等張化剤、軟膏基剤、オイル、溶解補助剤、吸収促進剤、接着剤、噴霧剤などが挙げられる。 The additives, excipients, binding agents, lubricants, disintegrants, diluents, flavoring agents, coloring agents, solubilizers, suspending agents, emulsifiers, preservatives, buffering agents, tonicity agents, ointment bases , oils, solubilizers, absorption enhancers, adhesives, and the like sprays.

【0019】式Iで示されるアミド誘導体及びその酸付加塩は、好酸球浸潤抑制作用を示すことから、それらの作用が効果を及ぼす他の疾患、たとえばアレルギー性鼻炎、じん麻疹、類天疱瘡、好酸球性膿疱性毛包炎、喘息などに有用であることが示唆される。 [0019] Amide derivatives and their acid addition salts represented by formula I, because they exhibit eosinophil infiltration inhibitory action, other diseases their action is an effect, for example, allergic rhinitis, urticaria, pemphigoid , eosinophilic pustular folliculitis, suggesting asthma useful for such. また、インターフェロンα、γを強力に誘起することから、多発性骨髄腫、腎癌、皮膚悪性腫瘍、膀胱癌、ヘアリー細胞白血病、慢性骨髄性白血病などの各種癌疾患と慢性関節リウマチにも有用である。 Further, interferon alpha, because it strongly induce gamma, multiple myeloma, renal cancer, malignant skin, bladder cancer, hairy cell leukemia, in various cancer diseases and rheumatoid arthritis, such as chronic myelogenous leukemia useful is there. さらに、B型、C型慢性活動性肝炎、単純ヘルペス性角膜炎、性器疣、尖圭コンジローマ、帯状疱疹、AIDSなどの各種ウイルス性疾患にも適応可能である。 Furthermore, B-type, C-type chronic active hepatitis, herpes simplex keratitis, genital warts, condyloma acuminata, herpes zoster, is applicable to various viral diseases such as AIDS.

【0020】式Iに属する最も好ましい化合物は次式で表される。 [0020] The most preferred compounds belonging to formula I is represented by the following formula.

【0021】N-[4-(4-Amino-1H-imidazo[4,5-c]quinoli [0021] N- [4- (4-Amino-1H-imidazo [4,5-c] quinoli
n-1-yl)butyl]-4-{[2-(dimethylamino)ethoxy]phenylme n-1-yl) butyl] -4 - {[2- (dimethylamino) ethoxy] phenylme
thyl}benzamide thyl} benzamide

【0022】 [0022]

【化3】 [Formula 3]

【0023】以下、化合物(II)と略す。 [0023] hereinafter referred to as compound (II).

【0024】この化合物は、例えば、以下の方法により合成される。 [0024] This compound is synthesized, for example, by the following method.

【0025】α−(2−ジメチルアミノエトキシ)−α The alpha-(2-dimethylaminoethoxy)-.alpha.
−フェニル−P−トルイル酸0.44g(1.47mmol) - phenyl -P- toluic acid 0.44 g (1.47 mmol)
をクロロホルム10mlに懸濁し、塩化チオニル0.21m Was suspended in chloroform 10 ml, thionyl chloride 0.21m
l(2.94mmol)を加え、2.5時間加熱還流する。 l a (2.94 mmol) was added and heated to reflux for 2.5 hours. 反応液を減圧下濃縮し、酸クロライド体の粗生成物を合成した後、1−(4−アミノブチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン0.38g(1.4 The reaction solution was concentrated under reduced pressure, to synthesize a crude product of the acid chloride thereof, 1- (4-aminobutyl)-1H-imidazo [4,5-c] quinolin-4-amine 0.38 g (1. 4
7mmol)をエタノール22mlと水15mlの混合溶媒に溶解し、1N−水酸化ナトリウム水溶液1.47mlを加えた後、氷冷下で先に得られた酸クロライド体のクロロホルム5ml懸濁溶液を加え、20分間撹拌させる。 The 7 mmol) was dissolved in a mixed solvent of ethanol 22ml of water 15 ml, was added to 1N- aqueous sodium 1.47ml hydroxide, chloroform 5ml suspension of previously obtained acid chloride thereof under ice-cooling was added, It is stirred for 20 minutes. 反応液を炭酸水素ナトリウム水溶液に注ぎ、クロロホルムさらにクロロホルム−メタノール(10:1(v/v))混液で抽出し、有機層を乾燥し、溶媒を留去し、残渣をアルミナカラムクロマトグラフィー(クロロホルム:メタノール=200:1〜30:1(v/v))で精製する。 The reaction solution was poured into aqueous sodium hydrogen carbonate solution, chloroform further chloroform - methanol (10: 1 (v / v)) was extracted with a mixture, the organic layer was dried, the solvent was evaporated, and the residue was purified by alumina column chromatography (chloroform : methanol = 200: 1 to 30: purified by 1 (v / v)). 最後にエーテルでトリチュレートして濾取し、化合物(II) Finally collected by filtration and triturated with ether, the compound (II)
0.44g(0.820mmol)を微橙白色粉末(mp:1 0.44g (0.820mmol) of Bidaidai white powder (mp: 1
10〜114℃)として得ることができる。 It can be obtained as ten to one hundred and fourteen ° C.).

【0026】式Iで示されるアミド誘導体及びその酸付加塩は、外用剤(軟膏剤、クリーム、ローション、ゲル剤)の基剤中で0.001〜10%、好ましくは0.0 The amide derivative and acid addition salts thereof represented by the I, external preparation from 0.001 to 10% (ointments, creams, lotions, gels) in bases, preferably 0.0
4〜1%になるように用いられる。 Used to be 4-1%.

【0027】この発明では、式Iで示されるアミド誘導体及びその酸付加塩が外用剤とするに際して、予め溶解・吸収促進剤に溶解して用いられる。 [0027] In this invention, when amide derivatives and acid addition salts thereof represented by the formula I is a external preparation, used by dissolving in advance dissolution and absorption enhancers. この発明の溶解・ Dissolution of the present invention,
吸収促進剤とは、好ましくは化合物を少なくとも0.0 The absorption enhancer, at least preferably the compound 0.0
1%以上の濃度に溶解しうるもので、かつ外用剤として製剤化された際に式Iで示されるアミド誘導体及びその酸付加塩を皮膚から吸収しうるものを意味する。 But it can be dissolved in a concentration of 1% or more, and the amide derivative and acid addition salts thereof represented by the formula I when it is formulated to mean those which can be absorbed through the skin as an external preparation. 換言すれば式Iで示されるアミド誘導体及びその酸付加塩に溶解能と吸収能を付与しうるものである。 In other words those capable of imparting a dissolving ability and absorption ability amide derivatives and their acid addition salts of formula I.

【0028】なお、溶解能または吸収能の一方のみを有するものも、この発明の溶解・吸収促進剤の範囲に包含されるものである。 [0028] Incidentally, even those with only one of the dissolving ability or absorption capacity, are intended to be encompassed in the scope of the dissolution and absorption enhancers of the present invention.

【0029】上記2つの要件を満たす基剤を種々検討した結果、次のものが溶解・吸収促進剤として挙げられる。 [0029] The two meet requirements result of various studies on bases, the following can be cited as dissolution and absorption enhancers.

【0030】1. [0030] 1. アルコール類(エタノール、1,3ブタンジオール、グリセリン等) 2. Alcohols (ethanol, 1,3-butanediol, glycerin, etc.) 2. 高級脂肪酸(イソステアリン酸、オレイン酸等) 3. Higher fatty acid (isostearic acid, and oleic acid) 3. 有機概念図上において有機性値が30〜1000、 Organic Conceptual organic value in drawing is 30 to 1000,
無機性値が50〜1000、有機性値に対する無機性値の比が0.5〜2.0の領域内にある溶解・吸収促進剤で、例えば、炭酸低級アルキレン類(炭酸プロピレン、 Inorganic value is 50 to 1000, in dissolution and absorption enhancer ratio of the inorganic value is within the region of 0.5 to 2.0 for the organic value, for example, carbonate lower alkylenes (propylene carbonate,
炭酸エチレン等);界面活性剤(ソルビタンモノラウレート(SP−20)、ソルビタンモノステアレート(S Ethylene carbonate); surfactants (sorbitan monolaurate (SP-20), sorbitan monostearate (S
P−60)、DMSO等);モノグリセリド(モノステアリン酸グリセリル(MGS)、モノオレイン酸グリセリル(MGO));クロタミトン。 P-60), DMSO, etc.); monoglyceride (glyceryl monostearate (MGS), glyceryl monooleate (MGO)); crotamiton.

【0031】4. [0031] 4. これらの混合物 本明細書において、有機概念図とは、すべての有機化合物の根源をメタン(CH 4 )とし、ほかの化合物はすべてメタンの誘導体とみなしてその炭素数、置換基、変態部、環などにそれぞれ一定の数値を設定し、そのスコアを加算して有機性値及び無機性値を求め、この値を有機性値をχ軸、無機性値をy軸にとった図上にプロットしていくものである。 In these mixtures the specification, the organic conceptual diagram, the root of all organic compounds and methane (CH 4), the number of carbon atoms is regarded as a derivative of all other compounds methane, substituents, transformation unit, ring each set certain numerical etc., determine the organic value and the inorganic value by adding the scores, and plot this value organic value χ axis, the inorganic value on the diagram taken on the y-axis and those go.

【0032】この有機概念図は藤田穆氏の考案によるものであり、その詳細はKUMAMOTO PHARMA [0032] The organic conceptual diagram is due to the invention of Mr. Atsushi Fujita, the details of which are KUMAMOTO PHARMA
CEUTICAL BULLETIN,第1号、第1〜 CEUTICAL BULLETIN, No. 1, first to
16項(1954年)、化学の領域、第11巻、第10 16 Section (1954), Chemistry of regions, Vol. 11, No. 10
号、719〜725項(1957年)、フレグランスジャーナル、第34号、第97〜111項(1979 No. Section 719-725 (1957), Fragrance Journal, No. 34, Section 97-111 (1979
年)、フレグランスジャーナル、第50号、第79〜8 Year), Fragrance Journal, No. 50, No. 79-8
2項(1981年)などに説明されている。 Such as are described Section 2 (1981).

【0033】従って、各化合物の有機概念図はこれらの文献に記載の手法に従って、容易に求めることができる。 [0033] Therefore, the organic conceptual diagram of each compound may be according to the procedure described in these documents, easily determined.

【0034】化合物(II)に好適に用いられる溶解・吸収促進剤とその有機性値と無機性値を表1に示す。 [0034] The compounds dissolution and absorption-promoting agent suitably used in (II) and its organic value and the inorganic value shown in Table 1.

【0035】 [0035]

【表1】 [Table 1]

【0036】一方、化合物(II)に上述した有機性値および無機性値の範囲外で、一般的に使用される溶解基剤、例えば乳酸セチル、セバシン酸ジエチル、オリーブオイル、ヤシ油(ミグリオール812)等を用いると溶解性が著しく悪く、溶解・吸収促進剤として適さない。 On the other hand, outside the range of the above-mentioned organic value and the inorganic value to the compound (II), dissolving medium commonly used, for example cetyl lactate, diethyl sebacate, olive oil, coconut oil (Miglyol 812 ) is remarkably poor solubility and use of such unsuitable as a dissolution and absorption enhancers.

【0037】これらの有機性値と無機性値を表2に示す。 [0037] These organic value and the inorganic value are shown in Table 2.

【0038】 [0038]

【表2】 [Table 2]

【0039】この発明では、式Iで示されるアミド誘導体及びその酸付加塩を含有する溶液(溶解、吸収促進剤中)を、外用剤の基剤を用いて当該分野で公知の手段を用いて製剤化される。 [0039] In this invention, a solution containing the amide derivative and acid addition salts thereof represented by the formula I (dissolved, absorbed in promoting agent), using means known in the art using a base, external preparations It is formulated. 基剤としては、油脂性基剤(白色ワセリン、流動パラフィン、サラシミツロウ、ひまし油等)が挙げられる。 As a base, oleaginous base (white Vaseline, liquid paraffin, white beeswax, castor oil, etc.). これは、適宜組み合わせて用いるのが好ましい。 This is preferably used in combination as appropriate.

【0040】この発明の外用剤は、上記基剤に加えて、 The external preparation of the present invention, in addition to the above base,
香料、着色剤、防腐剤、高級アルケン酸のような吸収促進剤など外用剤に使用しうる他の添加物や、他の皮膚疾患に有効な薬剤が含まれてもよい。 Perfumes, coloring agents, preservatives, other additives and may include an agent effective in the treatment of other skin diseases which may be used in external preparations such as absorption accelerators such as higher alkenoic acid.

【0041】この発明の1つの観点によれば、式Iで示されるアミド誘導体及びその酸付加塩を溶解・吸収促進剤に溶解し、得られる溶液と基剤とを混合し、得られる混合物を攪拌または加熱攪拌し、ついで冷却して外用剤を得ることからなる軟膏剤の製法が提供される。 [0041] According to one aspect of the present invention, by dissolving the amide derivative and acid addition salts thereof represented by the formula I in dissolved and absorption enhancers, was mixed with the resulting solution and base, the resulting mixture stirring or heating and stirring, preparation of ointment consisting in obtaining the external preparation is provided then cooled.

【0042】この方法で1以上の添加剤と、任意に、式Iで示されるアミド誘導体及びその酸付加塩の溶液に用いたのと同じかまたは異なる溶解・吸収促進剤の追加量とを、基剤と同時に加えてもよい。 [0042] 1 and more additives in this process, optionally, an additional amount of the same or different dissolution and absorption enhancer as used in a solution of the amide derivatives and their acid addition salts of formula I, it may be added simultaneously with the base.

【0043】なお、この発明の外用剤においては、式I [0043] It should be noted that, in preparation for external use of this invention relates to compounds of formula I
で示されるアミド誘導体及びその酸付加塩が一部結晶として存在する場合があるが、この場合もこの発明範囲内に包含される。 In it amide derivatives and their acid addition salts show may exist as part crystalline, also in this case it is included within the invention scope.

【0044】この発明の外用剤は皮膚の患部に1日1〜 The external preparation of the present invention is 1-1 days to the affected area of ​​the skin
6回塗布して使用する事ができる。 6 times applied to can be used.

【0045】 [0045]

【実施例】実施例1 本発明による5%化合物(II)軟膏を以下の成分・方法により調整した。 EXAMPLES 5% compound according to example 1 present invention (II) ointment was prepared by the following components or methods.

【0046】化合物(II)5gを、ソルビタンモノラウレート(SP−20)25gに80℃で加熱溶解した(A液)。 [0046] Compound (II) 5 g, sorbitan monolaurate (SP-20) was heated and dissolved at 80 ° C. to 25 g (A solution). 白色ワセリン70gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes to those dissolved by heating white petrolatum 70g at 80 ° C., then mixed while cooling to room temperature.

【0047】実施例2 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0047] was prepared with 1% compound (II) the following components or methods to ointment according to Example 2 the present invention.

【0048】化合物(II)1gを、ソルビタンモノラウレート(SP−20)10gに80℃で加熱溶解する(A液)。 [0048] Compound (II) 1 g, sorbitan monolaurate (SP-20) were dissolved by heating at 80 ° C. to 10 g (A solution). 白色ワセリン89gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes to those dissolved by heating white petrolatum 89g at 80 ° C., then mixed while cooling to room temperature.

【0049】実施例3 本発明による0.2%化合物(II)軟膏を以下の成分・ The components of the following Example 0.2% Compound according to 3 the invention (II) Ointment -
方法により調整した。 It was adjusted by the method.

【0050】化合物(II)0.2gを、ソルビタンモノラウレート(SP−20)10gに80℃で加熱溶解する(A液)。 [0050] Compound (II) 0.2 g, sorbitan monolaurate (SP-20) were dissolved by heating at 80 ° C. to 10 g (A solution). 白色ワセリン89.8gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes to those dissolved by heating white petrolatum 89.8g at 80 ° C., then mixed while cooling to room temperature.

【0051】実施例4 本発明による0.04%化合物(II)軟膏を以下の成分・方法により調整した。 [0051] 0.04% compound according to Example 4 the present invention (II) is an ointment was prepared by the following components or methods.

【0052】化合物(II)0.04gを、ソルビタンモノラウレート(SP−20)10gに80℃で加熱溶解する(A液)。 [0052] Compound (II) 0.04 g, sorbitan monolaurate (SP-20) were dissolved by heating at 80 ° C. to 10 g (A solution). 白色ワセリン89.96gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes to those dissolved by heating white petrolatum 89.96g at 80 ° C., then mixed while cooling to room temperature.

【0053】実施例5 本発明による0.008%化合物(II)軟膏を以下の成分・方法により調整した。 [0053] was prepared by the following components, the method Example 5 This 0.008% or compounds according to the invention (II) ointment.

【0054】化合物(II)0.008gを、ソルビタンモノラウレート(SP−20)10gに80℃で加熱溶解する(A液)。 [0054] Compound (II) 0.008 g, sorbitan monolaurate (SP-20) were dissolved by heating at 80 ° C. to 10 g (A solution). 白色ワセリン89.992gを80℃ White petrolatum 89.992g 80 ℃
で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 In and stirred for 10 minutes was added to solution A to that dissolved by heating and then mixed while cooling to room temperature.

【0055】実施例6 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0055] was prepared with 1% compound (II) the following components or methods to ointment according to Example 6 the present invention.

【0056】化合物(II)1gを、ソルビタンモノステアレート(SP−60)10gに80℃で加熱溶解する(A液)。 [0056] Compound (II) 1 g, sorbitan monostearate (SP-60) were dissolved by heating at 80 ° C. to 10 g (A solution). ポリオキシエチレン(10)硬化ひまし油(以下、HCO−10と略す)5g、白色ワセリン84 Polyoxyethylene (10) hydrogenated castor oil (hereinafter, abbreviated as HCO-10) 5 g, white petrolatum 84
gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 A solution was added and stirred for 10 minutes g in those heated and dissolved at 80 ° C., then mixed while cooling to room temperature.

【0057】実施例8 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0057] was prepared with 1% compound (II) the following components or methods to ointment according to Example 8 the invention.

【0058】化合物(II)1gを、モノステアリン酸グリセリル(MGS)10gに80℃で加熱溶解する(A [0058] Compound (II) 1 g, dissolved by heating at 80 ° C. in glyceryl monostearate (MGS) 10g (A
液)。 liquid). HCO−10 5g、白色ワセリン84gを80 HCO-10 5 g, white petrolatum 84 g 80
℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes that were heated and dissolved at ° C., then mixed while cooling to room temperature.

【0059】実施例9 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0059] was prepared with 1% compound (II) the following components or methods to ointment according to Example 9 the present invention.

【0060】化合物(II)1gを、モノオレイン酸グリセリル(MGO)10gに80℃で加熱溶解する(A [0060] Compound (II) 1 g, dissolved by heating at 80 ° C. to glyceryl monooleate (MGO) 10g (A
液)。 liquid). HCO−10 5g、白色ワセリン84gを80 HCO-10 5 g, white petrolatum 84 g 80
℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 Stirring solution A was added 10 minutes that were heated and dissolved at ° C., then mixed while cooling to room temperature.

【0061】実施例10 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0061] 1% compound according to Example 10 This invention (II) ointment was prepared by the following components or methods.

【0062】化合物(II)1gを、1,3−ブタンジオール5gに70℃で加熱溶解した(A液)。 [0062] Compound (II) 1 g, was dissolved by heating at 70 ° C. in 1,3-butane diol 5 g (A solution). 一方、ステアリン酸3g、ステアリルアルコール0.5g、ミツロウ0.5g、グリセリルモノステアレート3g、HCO Meanwhile, stearic acid 3g, stearyl alcohol 0.5g, beeswax 0.5g, glyceryl monostearate 3g, HCO
−10 0.5g、セバシン酸ジエチル0.25g、白色ワセリン86.25gを70℃の加温下で溶解し均一に混合した(B液)。 -10 0.5 g, diethyl sebacate 0.25 g, was dissolved in warm under the white petrolatum 86.25g 70 ℃ were uniformly mixed (B solution). 次に、B液を60℃の加温下で攪拌しながらA液を加え10分間攪拌し、室温に冷却しながら混合した。 Then, stirring solution A was added for 10 minutes while the solution B was stirred at heating under 60 ° C., and mixed while cooling to room temperature.

【0063】実施例11 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0063] was prepared with 1% compound (II) the following components or methods to ointment according to Example 11 present invention.

【0064】化合物(II)1gを、80℃で加熱したソルビタンモノラウレート(SP−20)5gとクロタミトン2gの混合溶液で溶解した(A液)。 [0064] Compound (II) 1 g, sorbitan and heated at 80 ° C. monolaurate (SP-20) was dissolved in a mixed solution of 5g and crotamiton 2 g (A solution). HCO−10 HCO-10
5g、白色ワセリン87gを80℃で加熱溶解したものにA液を加え10分間攪拌し、次いで室温に冷却しながら混合した。 5g, stirring solution A was added 10 minutes white petrolatum 87g to those dissolved by heating at 80 ° C., then mixed while cooling to room temperature.

【0065】実施例12 本発明による1%化合物(II)クリームを以下の成分・ [0065] Component 1% compound according to Example 12 the present invention (II) is a cream or less,
方法により調整した。 It was adjusted by the method.

【0066】化合物(II)1gを、80℃で加熱したイソステアリン酸10gで溶解後、80℃下でベンジルアルコール2g、セチルアルコール2.2g、ステアリルアルコール3.1g、Polysorbate60 2.55g、 [0066] Compound (II) 1 g, was dissolved in isostearic acid 10g was heated at 80 ° C., benzyl alcohol 2g under 80 ° C., cetyl alcohol 2.2g, stearyl alcohol 3.1 g, Polysorbate 60 2.55 g,
ソルビタンモノステアレート0.45gを添加し攪拌溶解した(A液)。 It was added sorbitan monostearate 0.45g stirred solution (A solution). 一方、グリセリン2g、メチルパラベン0.2g、プロピルパラベン0.02g、精製水7 Meanwhile, glycerin 2g, methylparaben 0.2 g, propylparaben 0.02 g, purified water 7
6.48gを80℃の加温下で溶解し均一に混合した(B液)。 It was dissolved in warm under 6.48 g 80 ° C. were uniformly mixed (B solution). A液、B液をほぼ同じ温度(75℃)に加温し、A液にB液を加えAce Homogenizer(AM-3)(日本精機製作所)で10分間混合(12000rpm)した。 A solution, B solution warmed about the same temperature (75 ° C.), B solution was added to Solution A Ace Homogenizer (AM-3) were mixed for 10 minutes (12000 rpm) in (Nippon Seiki Seisakusho).
次いで、水冷しながら低回転で15分間混合した。 Then mixed for 15 minutes at low rpm with water cooling.

【0067】実施例13 本発明による1%化合物(II)ローションを以下の成分・方法により調整した。 [0067] was prepared by the following components, the method 1% compound (II) lotion according to Example 13 present invention.

【0068】化合物(II)1gを、70℃で加熱した1,3−ブタンジオール69gで溶解し、精製水30g [0068] Compound (II) 1 g, was dissolved in heated 1,3-butanediol 69g at 70 ° C., purified water 30g
を加え攪拌した。 And the mixture was stirred.

【0069】実施例14 本発明による1%化合物(II)ローションを以下の成分・方法により調整した。 [0069] was prepared by the following components, the method 1% compound (II) lotion according to Example 14 present invention.

【0070】化合物(II)1gを、70℃で加熱した1,3−ブタンジオール49gで溶解し、精製水50g [0070] Compound (II) 1 g, was dissolved in heated 1,3-butanediol 49g at 70 ° C., purified water 50g
を加え攪拌した。 And the mixture was stirred.

【0071】実施例15 本発明による1%化合物(II)ローションを以下の成分・方法により調整した。 [0071] was prepared by the following components, the method 1% compound (II) lotion according to Example 15 present invention.

【0072】化合物(II)1gを、70℃で加熱したソルビタンモノラウレート(SP−20)10gで溶解し、流動パラフィン89gを加え攪拌した。 [0072] Compound (II) 1g, 70 ℃ a heated sorbitan monolaurate (SP-20) was dissolved in 10 g, was added and stirred liquid paraffin 89 g.

【0073】比較例1 本発明による1%化合物(II)軟膏を以下の成分・方法により調整した。 [0073] The 1% Compound according to Comparative Example 1 present invention (II) ointment was adjusted by the following components or methods.

【0074】化合物(II)1gを、ミグリオール812 [0074] Compound (II) 1g, Miglyol 812
10gに80℃で加熱し懸濁した(A液)。 It was heated at 80 ° C. was suspended in 10 g (A solution). 白色ワセリン89gを80℃で加熱溶解したものにA液を加え1 It added A solution obtained by heat dissolving white petrolatum 89g at 80 ° C. 1
0分間攪拌し、次いで室温に冷却しながら混合した。 It was stirred for 30 minutes and then mixed while cooling to room temperature.

【0075】次にこの発明の軟膏についての経皮吸収試験及び薬理試験について述べる。 [0075] Next described percutaneous absorption tests and pharmacological tests for the ointment of the present invention.

【0076】 インターフェロン誘起活性化合物(II)について、ヒトインターフェロン-α測定キット(大塚製薬)とヒトインターフェロン-γ測定キット(BioSource International)を使用してELISA法でIFN量を定量した結果、高いインターフェロン誘起活性を有することが確認された。 [0076] Interferon-induced active compound for (II), human interferon -α assay kit (Otsuka Pharmaceutical) and human interferon -γ assay kit (BioSource International) results of quantification of IFN amount by ELISA using a high interferon-induced to have activity was confirmed.

【0077】 経皮吸収性 (1)試験方法 動物は4週齢のヘアレスマウス(雄)を日本クレア(株)より購入し1週間の馴化期間の後実験に供した。 [0077] percutaneous absorption (1) Test Method animals were subjected to a 4-week-old hairless mice (male) in the experiment after the CLEA Japan (Ltd.) purchased from one week of acclimatization period.

【0078】経皮吸収性実験は引間知広らの方法(薬剤学,Vol.55(2),122-126,1995)に準じて行った。 [0078] percutaneous absorption experiment Tomohiro Hikima et al. (Pharmaceutics, Vol.55 (2), 122-126,1995) was carried out in accordance with.

【0079】マウスの背部皮膚を無傷の皮膚(インタクトスキン)状態で切り取り、縦型2セル型膜透過実験装置(VIDREZX)に取り付けた。 [0079] cut dorsal skin of mice intact skin (intact skin) state, attached to the vertical type 2 cell membrane permeation experimental apparatus (VIDREZX). 実施例2、実施例8及び比較例1の方法で調整した軟膏(300mg)をト゛ナーセルの皮膚上に加え、レセプターセルにはペニシリン(50 Example 2, was added ointment adjusted by the method of Example 8 and Comparative Example 1 (300 mg) onto the skin of de Nasser, the receptor cells are penicillin (50
U/ml)とストレプトマイシン(50μg/ml)を含むPBS U / ml) and streptomycin (50μg / ml) PBS
を満たした。 It was met. レセプター溶液を一定温度(37℃)に保ち、透過実験を行った。 Receptor solution was maintained at a constant temperature (37 ° C.), it was carried out permeation experiments. 経時的にサンプル口から100 From the time the sample port 100
μlサンプリングし、HPLCにより薬物を定量した。 Was μl sample was quantified drug by HPLC.

【0080】この結果より薬物皮膚透過速度を求めた。 [0080] was determined the drug skin permeation rate than this result.

【0081】(2)結果 表3に示すように実施例2及び実施例8の製剤が優れた経皮吸収性を示すことが、確認された。 [0081] (2) indicate the results table 3 excellent formulation of Example 2 and Example 8, as shown in percutaneous absorbability was confirmed.

【0082】 [0082]

【表3】 [Table 3]

【0083】 皮膚好酸球浸潤抑制作用マウス皮膚好酸球浸潤モデルにより本製剤の好酸球浸潤抑制効果を調べる。 [0083] Check eosinophilic infiltration inhibitory effect of the formulation by cutaneous eosinophilic infiltration inhibitory action mouse skin eosinophilia model.

【0084】(1)試験方法 動物飼育方法 動物は4週齢のBalb/cマウス(雄)を日本クレア(株) [0084] (1) Test Method animal husbandry animals of 4-week-old Balb / c mice (male) CLEA Japan (Ltd.)
より購入し室温23±2℃、湿度50±10%(照明時間(8:00-20:00)の条件下で1週間以上の馴化期間の後に実験に供した。実験はすべて非絶食下で行い、被験物投与後の実験期間中は自由に水及び飼料を摂取させた(実験時の体重:18〜32g))。 More purchase at room temperature 23 ± 2 ° C., humidity 50 ± 10% (illumination time (8: 00-20: 00.) Was used in the experiment after 1 week or more acclimatization period under the conditions of the experiment in all non-fasting performed, the duration of the experiment after test article administration was libitum water and food (in the experiment body weight: 18~32g)).

【0085】感作及び惹起 タンパク量10mg相当のダニ抽出物-Dp (コスモバイオ )にRO水3.8ml、生理食塩水1.2mlを加えタンパク質量2mg/mlの溶液(原液)を調製した。 [0085] Sensitization and eliciting protein content 10mg equivalent of mite extract -Dp RO water 3.8ml in (Cosmo Bio) to prepare a saline 1.2ml added protein amount 2mg / ml solution (stock solution). 原液を生理食塩水にてタンパク質量500μg/mlに調製した溶液に百日せき菌液を40分の1容量添加したものを感作溶液とした。 What the Pertussis bacteria solution stock solution with physiological saline solution prepared to protein amount 500 [mu] g / ml was 1 volume addition of 40 minutes was sensitized solution. 感作はマイジェクター(テルモ社製)を用い、マウスの頸部の皮下にこの溶液を200μl投与することによって行った。 Sensitization with Maijekuta (manufactured by Terumo Corporation), was carried out by the solution 200μl administered to mice subcutaneously in the neck. この感作方法で初回感作を含め7日おきに3回感作を行った。 Was three times sensitization every 7 days, including the first sensitization in this sensitization method.

【0086】惹起は初回感作21日後に、生理食塩水で200μg/mlのタンパク濃度に調製したダニ抗原溶液を背部皮内にマイジェクター(テルモ社製)を用いて5 [0086] elicited first sensitization 21 days after mite antigen solution prepared protein concentration of 200 [mu] g / ml with physiological saline using a Maijekuta (manufactured by Terumo Corporation) in the dorsal intradermal 5
0μl投与することによって行った。 0μl was carried out by the administration.

【0087】皮膚回収及び病理標本の観察 惹起48時間後に頸椎脱臼によりマウスを屠殺し背部の皮膚を剥ぎ取り、マーキングした部分を中心に1cm四方に皮膚を切断した。 [0087] The skin recovery and cervical dislocation observed induced 48 hours after pathology specimens mice were sacrificed stripped dorsal skin was cut skin 1cm square around the marking portion. 回収した皮膚は10%中性ホルマリン緩衝液(コーニングの15ml遠沈管使用)に入れ1日以上室温で放置して固定した。 Collected skin was fixed to stand at room temperature over 1 day placed in 10% neutral buffered formalin (15ml centrifuge tube using a Corning). 固定した皮膚は、常法にしたがってパラフィン切片作成後、ルナ染色を施した(切り出しは体軸に対し垂直方向に皮膚サンプルの中央と頭側2mm上方の2ヶ所で行った)。 Fixed skin (Been cut in two places in the center and head side 2mm above the skin samples in the direction perpendicular to the body axis) in accordance with after creating paraffin sections were subjected to Luna stain conventional method. 標本の観察は光学顕微鏡(400倍)で、1切片1cm当たりの好酸球数を計測した。 Observation of the specimen with an optical microscope (400-fold), and counting the number of eosinophils per section 1 cm.

【0088】薬剤(被験化合物)による抑制は以下の式から算出した。 [0088] Inhibition by drugs (test compound) was calculated from the following equation.

【0089】 [0089]

【数1】 [Number 1]

【0090】各被験薬物の調製 実施例3〜5の軟膏剤を使用した。 [0090] Using the ointment of Example 3-5 of the test drug. また、吉草酸ベタメタゾンの外用剤は0.12%リンデロンV軟膏(シオノギ製薬)をそのまま使用した。 Furthermore, external preparations of betamethasone valerate was used as a 0.12% Rinderon V ointment (Shionogi &).

【0091】薬物投与方法 経皮投与(密封包帯法:Occlusive dressing technique [0091] Drug administration methods transdermal administration (occlusive dressing method: Occlusive dressing technique
(ODT)) マウスをエーテル麻酔して背部中央を電気バリカンで皮膚を傷つけないように除毛した。 (ODT)) were shaved so as not to injure the skin with electric clippers dorsal central and ether anesthetized mice. 背部中央の惹起箇所にあたる部分にあらかじめ油性マジックで印を付けた。 Marked in advance permanent marker on a portion corresponding to elicit part of the back center. 薬剤(被験化合物)の塗布は、背部の印をつけた部分を中心に前投与では3cm四方に、惹起後は惹起部分を中心に2cm四方に塗布した。 Coating agents (test compound) in 3cm square at predose be mainly marked back, after the induction was applied to 2cm square around the raised portion. さらに、塗布部を覆うようにポリエチレン製の不透性シートをのせ伸縮性テープ(Johnso Further, elastic tape placed a polyethylene impermeable sheet to cover the application part (Johnso
n & Johnson MEDICAL INC:エラスコチン)で固定した。 n & Johnson MEDICAL INC: Erasukochin) were fixed in. 対照群は基材のみを塗布した。 The control group was applied only to the base material.

【0092】投与量は一匹当たり50mg/dayとし、投与スケジュールは以下に示したように惹起前日より4日間連投した。 [0092] The dosage and one animal per 50 mg / day, administration schedule was Rento 4 days from eliciting the previous day, as shown below.

【0093】惹起前々日 → 惹起日(惹起直後)→ [0093] raised before two days → caused Date (immediately after induced) →
惹起翌日(計3回) (2)結果 実施例3〜5、0.12%吉草酸ベタメタゾン軟膏の各被験薬物のダニ惹起マウス皮膚好酸球浸潤反応に対する抑制効果を表4に示す。 It raised the following day (a total of three times) (2) Results Example 3~5,0.12% betamethasone valerate inhibitory effect against mite induced mouse skin eosinophilic infiltration reaction of each test drug ointment shown in Table 4. 実施例3、4の軟膏は好酸球浸潤を吉草酸ベタメタゾン軟膏(ステロイド)と同等に抑制した(表4)。 Ointment Examples 3 and 4 were equally inhibited the eosinophil infiltration betamethasone valerate ointment (steroid) (Table 4).

【0094】 [0094]

【表4】 [Table 4]

【0095】 [0095]

【発明の効果】上述した通り、本発明により新規な外用製剤が得られる。 [Effect of the Invention] As described above, novel topical formulations are obtained by the present invention. 本製剤に含まれるアミド誘導体は強力なインターフェロン(α、γ)誘起作用を有し、皮膚好酸球浸潤抑制効果により特にアトピー性皮膚炎の治療に有用である。 Amide derivatives included in the present formulation has potent interferon (alpha, gamma) induced effects, particularly useful for the treatment of atopic dermatitis by skin eosinophilic infiltration inhibitory effect.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 上田 美江子 神奈川県足柄上郡中井町井ノ口1500番地 テルモ株式会社内 ────────────────────────────────────────────────── ─── of the front page continued (72) inventor Mieko Ueda Kanagawa Prefecture ashigarakami district Nakai-cho, Inokuchi 1500 address Terumo within the Corporation

Claims (4)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】下記式Iで示されるアミド誘導体及びその医薬的に許容しうる酸付加塩と溶解・吸収促進剤、及び基剤よりなる外用剤。 1. A following amide derivatives and their pharmaceutically acceptable acid addition salt with a solubility-absorption enhancer represented by I, and an external preparation consisting of base. 【化1】 [Formula 1] (式I中、R 1およびR 2は炭素数1から6の分岐していてもよいアルキル基を表し、またR 1とR 2は一つになって環を形成していてもよい。またR 1またはR 2のどちらかが、X、Yあるいはメチレン鎖中の任意の原子と一つになって環を形成していてもよい。XおよびYは独立して、酸素原子、S(О)p(pは0から2の整数を表す。)、NR 4 、CR 5 =CR 6 、CR 78あるいは置換されていてもよいフェニレン基を表す。ここで、R 4 (Wherein I, R 1 and R 2 may form a represents an alkyl group which may be branched from 1 to 6 carbon atoms, and R 1 and R 2 are taken as one ring. The either R 1 or R 2, X, good .X and Y may form a ring become one and any atom in Y, or a methylene chain is independently an oxygen atom, S (o ) p (p is an integer of 0 to 2.) represents NR 4, CR 5 = CR 6 , CR 7 R 8 or optionally substituted phenylene group. wherein, R 4,
    5 、R 6 、R 7およびR 8は独立して、水素原子、低級アルキル基、水酸基、低級アルコキシ基、アミノ基、モノあるいはジ低級アルキル置換アミノ基、カルボキシル基、低級アルコキシカルボニル基、置換されていてもよい芳香環基、あるいは置換されていてもよい複素環基を表す。 R 5, R 6, R 7 and R 8 are independently hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, mono- or di-lower alkyl-substituted amino group, a carboxyl group, lower alkoxycarbonyl group, a substituted which may be an aromatic ring group, or represents a optionally substituted heterocyclic group. Zは芳香環または複素環を表し、低級アルキル基、水酸基、低級アルコキシ基あるいはハロゲンのような置換基を有していてもよい。 Z represents an aromatic ring or a heterocyclic ring, lower alkyl group, a hydroxyl group, which may have a substituent such as a lower alkoxy group or a halogen. 3は水素原子、置換されていてもよいフェニル基、低級アルキル基(フェニル基、フェノキシ基、ベンジルオキシ基、低級アルコキシ基、アミノ基、モノあるいはジ低級アルキル置換アミノ基、カルボキシル基、あるいは低級アルコキシカルボニル基で置換されていてもよい。)を表す。 R 3 is a hydrogen atom, an optionally substituted phenyl group, a lower alkyl group (a phenyl group, a phenoxy group, a benzyloxy group, a lower alkoxy group, an amino group, mono- or di-lower alkyl-substituted amino group, a carboxyl group or a lower, alkoxy may be substituted with a carbonyl group.) represents the. g、iおよびkは独立して0から6の整数を表し、h、jおよびlは独立して0または1を表し、mは0から5の整数を、n g, i and k represents an integer of from 0 independently 6, h, j and l is 0 or 1 independently an integer of m from 0 5, n
    は2から12の整数を表す。 Represents an integer of from 2 to 12. )
  2. 【請求項2】請求項1に記載のアミド誘導体及びその医薬的に許容しうる酸付加塩の外用剤中における含量が0.001〜10%(w/w)である請求項1に記載の外用剤。 2. A according to claim 1 content in the external preparation of the amide derivatives and their pharmaceutically acceptable acid addition salt according is 0.001~10% (w / w) in claim 1 external preparation.
  3. 【請求項3】請求項1に記載のアミド誘導体及びその医薬的に許容しうる酸付加塩を溶解しうる溶解・吸収促進剤がアルコール類(エタノール、エチレングリコール、 3. A derivative according to claim 1 and a pharmaceutically dissolution and absorption promoters capable of dissolving acceptable acid addition salts are alcohols (ethanol, ethylene glycol,
    プロピレングリコール、1,3ブタンジオール、グリセリン等)および/または、高級脂肪酸(イソステアリン酸、オレイン酸等)および/または、本文に定義する有機概念図上において有機性値が30〜1000、無機性値が50〜1000、有機性値に対する無機性値の比が0.5〜2.0の領域内にある溶解・吸収促進剤から選ばれる少なくとも一種を含有することを特徴とする請求項1または2記載の外用剤。 Propylene glycol, 1,3-butanediol, glycerin, etc.) and / or a higher fatty acid (isostearic acid, oleic acid) and / or the organic value in organic conceptual diagram defining the body is 30 to 1000, inorganic value but 50 to 1000, claim, characterized in that it contains at least one ratio of the inorganic value for organic value is selected from the dissolution and absorption enhancer in the region of 0.5 to 2.0 1 or 2 external preparation as described.
  4. 【請求項4】溶解・吸収促進剤の外用剤中における含量が、0.1〜70%(w/w)である請求項1〜3のいずれか1項に記載の外用剤。 Content in external preparation in wherein dissolution and absorption enhancer, external preparation according to claim 1 which is 0.1~70% (w / w).
JP2165298A 1998-02-03 1998-02-03 Preparation for external use containing amide derivative inducing interferon Granted JPH11222432A (en)

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